5-acyl-2,3-dihydrobenzothiophene-2-carboxylic acids

ABSTRACT

5-ACYL-BENZOFURAN-2-CARBOXYLIC, 5-ACYL-BENZOTHIOPHENE2-CARBOXYLIC ACIDS AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF WITH BASES, WHICH COMPOUNDS HAVE VALUABLE DIURETIC AND SIMULTANEOUSLY SALURETIC AS WELL AS ANTI-TUSSIVE ACTIVITIES, THERAPEUTIC COMPOSITIONS CONTAINING SUCH COMPOUNDS ARE AFORESAID OR THEIR PHARMACEUTICALLY ACCEPTABLE SALTS WITH BASES AS WELL AS METHODS FOR PRODUCING SMULTANEOUSLY DIURETIC AND SALURETIC EFFECTS AND FOR INHIBITING TUSSIVE IRRITATION IN MAMMALS. ILLUSTRATIVE EMBODIMENTS EXHIBITING PRIMARILY ANTITUSSIVE AND SIMULTANEOUS DIURETIC AND SALURETIC EFFECTS RESPECTIVELY ARE 2,3-DIHYDRO5-BUTYRYL-6-METHYL-BENZOFURAN-2-CARBOXYLIC ACID AND 2,3DIHYDRO-5-BUTYRYL-6,7-DIMETHYL-BENZOFURAN - 2 - CARBOXYLIC ACID.

United States Patent 3,751,430 S-ACYL-Z,3-DIHYDROBENZOTHIOPHENE- Z-CARBOXYLIC ACIDS Bernard Libis, Saint Louis la Chaussee, France, and Ernst Habicht, Gberwil, Switzerland, assignors to Ciba-Geigy Corporation, Ardsley, N.Y.

N0 Drawing. Original application May 26, 1969, Ser. No. 827,941, now Patent No. 3,651,094, dated Mar. 21, 1972. Divided and this application Sept. 20, 1971, Ser. No. 182,164

Claims priority, applicatiranfiS/vgitzerland, May 30, 1968,

s 3 8 Int. c1. A611; 27700; com 63/22, /34

US. Cl. 260-3305 5 Claims ABSTRACT OF THE DISCLOSURE This is a division of application Ser. No. 827,941, filed May 26, 1969, now US. Pat. No. 3,651,094, patented Mar. 21, 1972.

The present invention relates to new heterocyclic carboxylic acids having valuable pharmacological properties. More particularly, the invention pertains to new S-acylbenzofuran-Z-carboxylic acids, 5 acyl-benzothiophene-Z- carboxylic acids and pharmaceutically acceptable salts thereof with bases which compounds exhibit anti-tussive and simultaneously diuretic and saluretic activities. In a further aspect the present invention provides therapeutic compositions consisting essentially of (1) a S-acyl-benzofuran-Z-carhoxylic acid or S-acyl-benzothiophene 2 carboxylic acid as aforesaid or a pharmaceutically acceptable salt thereof with a base and (2) a pharmaceutical carrier therefor. The invention also provides methods for producing simultaneously diuretic and saluretic efiects and inhibiting tussive irritation in mammals which comprise administering to said mammals, an efiective amount of a compound according to the invention or a pharmaceutically acceptable salt thereof with a base.

In accordance with the foregoing, the present invention provides, in its broadest aspect, a compound of the Formula I X ooorr wherein as well as pharmaceutically acceptable salts thereof with bases.

3,751,430 ?atented Aug. 7, 1973 In the above compounds, and in the starting materials referred to below, 2, occupies the 4- or fi-position and Z the 6- or 7-position, and R is for example the ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl, tert. butyl, pentyl, isopentyl, l-methylbutyl, l-ethylpropyl, 1,1-dimethylpropyl, hexyl, isohexyl, heptyl, isoheptyl or 1,1-diethyl propyl group.

A preferred sub-class of compounds according to the instant invention are those having the Formula I illustrated above wherein R is alkyl having from 2 to 7 carbon atoms,

X is oxygen, Y and Y are hydrogen and Z, and Z independently, are hydrogen or methyl as well as pharmaceutically acceptable salts thereof with bases.

Especially preferred compounds of Formula I are 2,3- dihydro 5 butyryl 6 methyl-benzofuran-Z-carboxylic acid, 2,3-dihydro 5 butyryl-6,7-dimethyl-benzofuran-2- carboxylic acid and 2,3-dihydro- 5 (2-ethyl-butyryl)-6- methyl benzoturan-Z-carboxylic acid as well as pharmaceutically acceptable salts thereof with bases.

The compounds of the present invention are prepared by reacting a compound of the Formula II Z2 (11) wherein X, Y Y Z and 2;, have the meaning given under Formula I, with a carboxylic acid halide of the Formula III 0 -Q. or with a carboxylic acid anhydride of the Formula IV wherein R has the meaning given under Formula I and Q is halogen; according to the Friedel-Crafts reaction and, optionally, converting the reaction product with an in organic or organic base into a salt thereof.

As halogen, Q is preferably chlorine or bromine. Suitable catalysts for the reaction according to Friedel-Crafts are, e.g. especially aluminium chloride and tin (IV)-chloride, also zinc chloride, concentrated sulfuric acid, phosphoric acid, polyphosphoric acid or pyrophosphoric acid. The stated acids are preferentially used where the acylation agent is a carboxylic acid anhydride. The reaction is preferably performed in a solvent. Suitable solvents are, e.g. aliphatic or cycloaliphatic hydrocarbons such as heptane or cyclohexane, nitrohydrocarbons such as nitromethane, nitrocyclohexane or nitrobenzene, or halogen hydrocarbons such as carbon tetrachloride, ethylene chloride, methylene chloride, o-dichlorobenzene and, moreover, carbon disulfide.

Suitable starting materials of the Formula II, wherein X is oxygen, are, e.g. compounds of which the radicals Y Y Z and 2;, correspond with groups listed under Formula I. Of these types of compounds, the 2,3-dihydro-benzofuran-Z-carboxylic acid [cp. R. Fittig and G. Ebert, Arm. Chem. 216, 116 (1883)] and the 2,3-dihydr0- 6-methoxybenzofuran-Z-carboxylic acid [cp. W. Will and P. Beck, Chem. Ber. 19, 1783 (1886)] are, for example, known. Further compounds of this series may be prepared e.g. starting with substituted 2-allyl phenols which are oxidised with peracetic acid to the corresponding 2- (2,3 epoxypropyl)-phenols and these are rearranged by heating into the corresponding 2,3 dihydro-2-hydroxymethyl-benzofurans, which are oxidised with potassium permanganate to corresponding 2,3-dihydrobenzofuran-2- carboxylic acids. For example, the 2,3-dihydro-6-chlorobenzofuran-Z-carboxylic acid is produced by this process, starting with 2-allyl-5-chlorophenol and by way of the intermediate products 2-(2,3-epoxypropyl)-5-chlorophenol and 2,3 dihydro 2-hydroxymethyl-6-chlorobenzofuran. Moreover, compounds of the Formula II can also be produced by reducing optionally substituted benzofuran 2- carboxylic acids, e.g. with sodium amalgam, to obtain corresponding 2,3-dihydro-benzofuran-Z-carboxylic acids. For example, the 2,3 dihydro-G-methylbenzofuran-2-carboxylic acid is produced according to this process, starting with the 6-methylbenzofuran-2-carboxylic acid [cp. K von Auwers, Ann. Chem. 408, 255 (1955 Starting materials of the Formula II wherein X is sulfur are produced by an analogous manner by reduction of the corresponding substituent benzo[b]thiophen-Z-carboxylic acid with sodium amalgam. Some of the benzo[b]thiophene-Z-carboxylic acids necessary as starting material, are already known, e.g. the 6-methyl-benzo[b]thiophene-Z- carboxylic acid (cp. Y. Matsuki, T. Kanda, Nippon Kagaku Zazshi, 86, 99-102 (1965)) and the others can be obtained in an analogous manner, for example by acylating the corresponding substituted benzo [b]thiophene. Substituted benzo[b]thiophene-Z-carboxylic acids can also be obtained by condensation of o-halogen benzene aldehydes to the corresponding substituted (o-halogen-benzyliden)-rhodanine and by boiling these with sodium hydroxide and if necessary heating with sodium methylate in dimethylene glycol at about ISO-160 (cp. M. D. Castle, R. G. Plevey and Y. C. Tatlow, J. Chem. Soc. 1968, 1225- 1277).

It has been found that the compounds of Formula I, which are novel possess valuable pharmacological properties in conjunction with a high therapeutic index. They exhibit in particular, antitussive and diuretic activity. The pharmacological activity of the compounds of the invention are determined in various standard tests with experimental animals. Thus antitussive activity is demonstrated by its inhibiting eflfect on induced tussive irritation in the cat, [cp. R. Domenjoz, Arch. exptl. Pathol. Pharmacol. 215, 19-24 (1952)]. After the intravenous administration, about 1 mg./kg. of the sodium salt of 2,3-dihydro-5-butyryl-6-methyl-benzofuran-2-carboxylic acid, inhibits during one hour, appreciably or completely, tussive irritation on the cat produced by electrical stimulation of the N. laryngeus superior.

The diuretic and saluretic activities are also shown by standard tests [cp. A. G. Stenger et a1., Schweiz. Met. Wochenschr. 89, 1126 (1959)]. These properties characterise the new compounds as being suitable for the treatment of disturbances caused by insufficient excretion of electrolytes, especially of sodium chloride. Such disturbances are the cause of oedema and hypertension. For example, the 2,3-dihydro-5-butyryl-6,7-dimethyl-benzofuran- 2-carboxylic acid in a dosage of 5 mg./kg. per os in the case of the dog, increases the excretion of sodium ions and chloride ions to a marked degree, whereas the excretion of potassium ions is increased to only a minor extent. A similar effect is demonstrated employing 2,3-dihydro-5(2- ethyl-butyryl)-6-methyl-benzofuran-2-carboxylic acid.

The toxicity of the compounds of the invention on oral administration is of favourably low order.

The new compounds of the Formula I and their pharmaceutically acceptable salts with bases are thus suitable as medicaments which can be administered orally, rectally or parenterally for the relief of tussive irritation and for the production of diuretic and saluretic effects. The pharmaceutically acceptable salts of the compounds of the invention may be prepared by any of the methods known in the art. To form the salts, it is possible to use inorganic or organic bases such as, e.g. alkali or alkaline-earth metal hydroxides, carbonates or bicarbonates, triethanolamine or choline. The daily dosages of free bases, or of pharmaceutically acceptable salts thereof, vary between 1 and 20 mg./kg. per os for mammals. Suitable dosage units such as drages, capsules, tablets, suppositories or ampoules, preferably contain 25-250 mg. of an active substance, according to the invention, or of a pharmaceutically acceptable salt thereof.

Dosage units for oral administration preferably contain as active substance between 20% and of a compound of the Formula I, or of a pharmaceutically acceptable salt thereof. They are produced by combining the active substance, e.g. with solid, pulverulent carriers such as lactose, saccharose, sorbitol, manuitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, optionally with the addition of lubricants, such as magnesium or calcium stearate or polyethylene glycols, to form tablets or drage cores. The latter are coated, e.g. with concentrated sugar solutions which can also contain, e.g. gum arabic, talcum and/or titanium dioxide, or with a lacquer dissolved in easily volatile organic solvents or mixtures of solvents. Dyestuffs can be added to these coatings, e.g. for distinguishing between varying dosages of active substance. Other suitable dosage units for oral administration are hard gelatine capsules as well as soft, closed capsules made of gelatine and a softener such as glycerin. The hard capsules preferably contain the active substance as a granulate in admixture with lubricants such as talcum or magnesium stearate and, optionally, stabilisers, such as sodium metabisulphite or ascorbic acid. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids, such as liquid polyethylene glycols, whereby stabilisers can likewise be added.

Also suitable for the treatment of coughing are, e.g. sucking tablets, and also forms not administered as a single dosage such as, e.g. cough syrup and cough drops prepared with the usual auxiliary agents.

Suitable dosage units for rectal administration are, e.g. suppositories consisting of a combination of a compound of the Formula I, or of a suitable salt thereof, with a neutral fatty foundation substance, or also gelatine rectal capsules containing a combination of the active substance with polyethylene glycols.

Ampoules for parenteral, especially intramuscular administration, and also intravenous administration, preferably contain a water-soluble salt of a compound of the Formula I as active substance, in a concentration of preferably 0.55%, optionally together with suitable stabilising agents and buffer substances, in an aqueous solution.

In accordance with the foregoing the present invention also provides a therapeutic composition consisting essentially of (1) a compound of the Formula I or a pharmaceutically acceptable salt thereof with a base and (2) a pharmaceutical carrier therefor.

Further, the invention provides methods for producing a simultaneous diuretic and saluretic effect in mammals and for inhibiting tussive irritation in mammals which methods comprise administering to said mammal an effective amount of a compound of the Formula I or a pharmaceutically acceptable salt thereof with a base.

Preferably, for such compositions and methods in the said compound of the Formula I R is alkyl having from 2 to 7 carbon atoms,

X is oxygen,

Y and Y are hydrogen and Z and Z independently, are hydrogen or methyl.

The preferred specific compound for the treatment of tussive irritation is 2,3-dihydro-5-butyryl-6-methyl-benzofuran-Z-carboxylic acid. For the production of simultaneous diuretic and saluretic effects 2,3-dihydro-5-butyryl- 6,7-dimethylbenzofuran-2-carboxylic acid and 2,3-dihydro-S-(Z-ethyl-butyryl) 6 methyl-benzofuran-Z-carboxylic acid are preferred.

The following examples will serve to further typify the nature of the present invention, but should not be construed as a limitation on the scope thereof. All temperatures are given in degrees centigrade.

EXAMPLE 1 (a) 25.2 g. of 2,3-dihydro6-methylbenzofuran-2-carboxylic acid are slurried with 135 ml. of nitrobenzene and, while stirring and cooling, 69.5 g. of aluminium chloride are added in portions and within 30 minutes, so that the temperature does not rise above At the same temperature, 22.3 g. of butyryl chloride are added dropwise within 30 minutes. The reaction mixture is then further stirred for 5 hours in an ice bath, allowed to stand for 16 hours at room temperature, heated for a further hour to 40 and then poured onto 500.0 g. of ice. To the obtained suspension are added 50 ml. of concentrated hydrochioric acid. After the aluminium chloride complex has decomposed, the reaction mixture is extrated three times with, each time, 150 ml. of ether. The ether extract is dried over sodium sulfate and concentrated by evaporation. The residue is slurried in hexane, shaken up, again separated from the hexane and recrystallised from benzene. The obtained 2,3-dihydro-5-hutyryl- 6-methylbenzofuran-Z-carboxylic acid melts at 14014l.

The starting compound of (a) is produced as follows:

(b) 35.0 g. of G-methylbenzofuran-Z-carboxylic acid [cp. K. von Auwers, Ann. Chem. 408, 225 (1915)] are dissolved in 500 ml. of a saturated, aqueous sodium hydrogen carbonate solution and the solution is cooled to 5 in an ice bath. 500.0 g. of 5% sodium amalgam are added, the reaction mixture is removed after 2 hours from the ice bath and is allowed to stand for 24 hours at 20. The solution is subsequently separated from the mercury, filtered and the filtrate adjusted to pH 1 with concentrated hydrochloric acid. The obtained precipitate is filtered off, washed with 300 ml. of water and dried. The obtained 2,3-dihydro 6 methylbenzofuran-Z-carboxylic acid melts at 157 and, after recrystallisation from methanol/water, at 158.

EXAMPLE 2 (a) Analogously to Example 1(a), the 2,3-dihydro- 7-chlorobenzofuran-Z-carboxylic acid is acylated with butyryl chloride in nitrobenzene, in the presence of aluminium chloride, to the 2,3-dihydro-5-butyryl-7-chlorobenzofuran-Z-carboxylic acid, M.P. 161 (from benzene).

The starting compound, the 2,3-dihydro-7-chlorobenzofuran-Z-carhoxylic acid, is produced as follows:

(b) 112.0 g. of 2-allyl-6-chlorophenol [cp. D. S. Tarbell and I. W. Wilson, I. Am. Chem. Soc. 64, 1066 (1942)] are added, while stirring, within 30 minutes to a carefully cooled mixture of 6.5 g. of anhydrous sodium acetate and 160.0 g. of 40% peracetic acid. The reaction temperature must not rise above -20 during 24 hours. An excess of aqueous, saturated sodium hydrogen carbonate solution is then added. The ethereal solution is washed with saturated, aqueous sodium hydrogen carbonate, sodium chloride and iron(II)-sulfate solution, so that the entire excess of peracetic acid is decomposed. (the exces peracetic acid is detected with potassium iodide in water). The ether solution is then dried over sodium sulfate and concentrated by evaporation. The residue, the crude 6-chloro-2-(2,3-epoxypropyl)-pheno1, is heated for minutes to 110 and the reaction mixture is distilled under high vacuum. The obtained 2,3-dihydro-2-hydroxymethyl-7-chlorobenzofuran boils at 101108/0.02 torr.

(c) 15.0 g. of 2,3-dihydro-2-hydroxymethyl-7-chlorobenzofuran are slurried in 120 m1. of 4 N sodium hydroxide solution by vigorous shaking and cooled to 5. A solution of 72.0 g. of potassium permanganate in 1.3 litres of water is then added, all at once, to the suspension and the latter, while cooling, vigorously shaken so that the temperature does not exceed 25. After the reaction mixture is decolorised it is filtered off from the manganese dioxide and this is Washed with 300 ml. of hot water. The cooled solution is adjusted to pH 1 with concentrated hydrochloric acid and then extracted three times with, each time, 500 m1. of ether. The ether solution is dried over sodium sulfate and concentrated by evaporation. The residue is recrystallised from carbon tetrachloride/ benzene, whereupon the 2,3-dihydro-7-chlorobenzofuran- Z-carboxylic acid melts at 145-146.

EXAMPLE 3 The following end products are obtained, analogously to Example 1(a), starting with butyryl chloride in the presence of aluminium chloride in nitrobenzene:

(a) From 2,S-dihydrobenzofuran-Z-carboxylic acid [cp. R. Fitting and G. Ebert, Ann. Chem. 216, 166 (1883)] is obtained the 2,3-dihydro-5-butyrylbenzofuran-Z-carboxylic acid, M.P. 133 (from acetic acid ethyl ester), and

(b) From 2,3 dihydro 6-rnethoxybenzofuran-2-carboxylic acid [cp. W. Will and P. Beck, Chem. Ber. 19, 1783 (1886)] is obtained the 2,3-dihydro-5-butyryl-6- methoxybenzofuran-Z-carboxylic acid, M.P. 170 (from toluene/acetic acid ethyl ester).

EXAMPLE 4 (a) The 2,3 dihydro-S-butyryl-6-chlorobenzofuran-2- carboxylic acid, M.P. (from benzene) is produced, analogously to Example 1(a), from the 2,3-dihydro-6- chlorobenzofuran-Z-carboxylic acid with butyryl chloride in the presence of aluminium chloride in nitrobenzene.

The starting material, the 2,3-dihydro-6-chlorobenzofuran-Z-carboxylic acid, is obtained as follows:

(b) Analogously to Example 2(b), the mixture of 2- allyl3-chlorophenol and 2-allyl-5-chlor0phenol [cp. W. N. White, C. D. Slater, J. Org. Chem. 2 6, 3631 (1961)] is converted to the mixture of 2,3-dihydro-2-hydroxymethyl 4 chlorobenzofuran and 2,3-dihyro-2-hydroxymethyl-6- chlorobenzofuran, which distills at 95-115 0.02 torr. The distillate is separated by elution chromatography through silica gel with acetic acid ethyl ester/benzene (3:100) as the elution agent.

The isolated 2,3-dihydro-Z-hydroxymethyl-6-chlorobenzofuran is then converted, analogously to Example 2(0) with potassium permanganate into the 2,3 dihydro-6- chlorobenzofuran-Z-carboxylic acid, M.P. 163 (from benzene).

EXAMPLE 5 Analogously to Example 1(a), the 2,3 dihydro-6- methyLbenzofuran-Z carboxylic acid is acylated with propionyl chloride in nitrobenzene in the presence of aluminum chloride to the 2,3-dihydro-5-propionyl-6-methyl-benzofuran-2-carboxylic acid, M.P. (from cyclohexane/ethyl acetate).

The starting compound, 2,3 dihydro-fi-methyl-henzofuran-2-carboxylic acid is produced as in Example 1(b).

EXAMPLE 6 (a) Analogously to Example 1(a), the 2,3-dihydro-7- methoxy-benzofurane-Z-carboxylic acid is acylated with butyryl chloride in nitrobenzene in the presence of aluminum chloride to the 2,3-dihydro5-butyryl-7-methoxy-benzofurane, M.P. 118 (from benzene).

The starting compound, 2,3-dihydro-7-methoxy-benzofurane-Z-carboxylic acid, is produced as follows:

(b) Analogously to Example 1(b), 7-methoxy-beuzofurane-Z-carboxylic acid [cf. F.M.C. Corp. Neth. 6500340, C. A. 64, 3485a] is dissolved in aqueous sodium hydrogen carbonate and reduced with sodium amalgam to the 2,3-dihydro-7-methoxy benzofurane-Z-carboxylic acid, M.P. 123 (from benzene).

7 EXAMPLE 1 Aanalogously to Example 1(a), the 2,3-dihydro 6- methyl-benzofurane 2-carboxylic acid is acylated with valeroyl chloride in nitrobenzene in the presence of aluminum chloride to the 2,3dihydro-5-valeroyl-6-methyl benzofurane-Z-carboxylic acid, M.P. 137 (from cyclohexane/ ethyl acetate).

The starting compound is produced as in Example 1(b).

EXAMPLE 8 (a) Analogously to Example 1(a), the 2,3-dihydro-6,7- dimethyl-benzofuran 2-carboxylic acid is acylated with butyryl chloride in the presence of aluminum chloride and in nitrobenzene to the 2,3-dihydro-5-butyryl-6,7-dimethylbenzofuran-Z-carboxylic acid, M.P. 148 (from ethyl acetate).

The starting compound, 2,3-dihydro-6,7-dimethyl-benzofuran 2-carboxylic, is produced as follows:

(b) 45.0 g. of 2,3-dimethyl-phenol and 50.0 g. of malic acid were pulverised and thoroughly mixed. The mixture was added to 100 ml. of concentrated sulfuric acid and gradually warmed with stirring so that the reaction temperature had reached 130 after 30 minutes. The solution was kept at this temperature, for a further 30 minutes, poured into 1 kg. of ice and the resulting suspension stirred for 30 minutes. The crystalline precipitate obtained was filtered under suction and recrystallised from ethanol.

7,8-dimethyl-coumarin was obtained melting at 128- 130 C.

(c) 34.8 g. of the 7,8-dimethyl-courmarin obtained under (b) was dissolved in 60 ml. of chloroform. To this solution was added, dropwise, under stirring and occasional cooling with ice, a solution of 32.5 g. of bromine in 20 ml. of chloroform at a reaction temperature of 20-25 C. The mixture was stirred for a further 20 minutes at room temperature and the chloroform then completely removed by evaporation under vacuum. The residue was added in portions to a slurry comprising 90.0 g. of potassium hydroxide in 300 ml. of ethanol, the temperature being held at between 30 and 40 with ice cooling. The mixture was stirred for 30 minutes at 40 and 30 minutes at 80 and then poured into 2 litres of ice water. The aqueous alkaline solution was washed twice with about 400 ml. of ether and acidified to a pH of 2-3 with concentrated hydro chloric acid. The suspension obtained was stirred for one half hour at room temperature. The crystalline precipitate formed was collected by filter under suction and recrystallised from ethanol.

6,7-dimethyl-benzoturane-Z-carboxylic acid, M.P. 237- 239 was obtained.

(d) Analogously to Example 1(b), the 6,7-dimethylbenzofuran-Z-carboxylic acid is dissolved in aqueous sodium hydrogen carbonate and reduced with sodium amalgan to the 2,3 dihydro-6,7-dimethyl-benzofuran-Z-carboxylic acid, M.P. 182 (from ethanol).

EXAMPLE 9 Analogously to Example 1(a), the 2,3-dihydro-6-methyl-benzofuran-Z-carboxylic acid is acylated with 2-ethyl butyryl chloride in nitrobenzene in the presence of aluminum chloride chloride to the 2,3 dihydro S-(Z-ethylbutyryl) 6 methyl-benzofuran-Z-carboxylic acid, M.P. 104 (from hexane).

The starting compound is produced as in Example 1(b) EXAMPLE 10 Analogously to Example 1(a), the 2,3-dihydro-3,6-dimethyl-benzofuran-2-carboxylic acid [cf. Fries, Pinke- Wirth, A. 362, 52] is acylated with butyryl chloride in nitrobenzene in the presence of aluminum chloride to the 2,3 dihydro 3,6-dimethyl-5butyryl-benzofuran-Z-carboxylic acid, M.P. 98-100 (from benzene).

8 EXAMPLE 11 Analogously to Example 1(a), the 2,3-dihydro-6- methyl-benzofuran-Z-carboxylic acid is acylated with isovaleroyl chloride in nitrobenzene in the presence of aluminum chloride to the 2,3-dihydro-5-iso-valeroyl-6- methyl-benzofuran-Z-carboxylic acid, M.P. 132 (from benzene).

The starting compound is produced as in Example 1(b).

EXAMPLE 12 (a) Analogously to Example 1(a), the 2,3-dihydro-6- methylbenzofuran-Z-carboxylic acid is acylated with hexanoyl chloride in nitrobenzene in the presence of aluminum chloride to the 2,3-dihydro-5-hexanoyl-6- rnethyl-benzofuran-Z-carboxylic acid, M.P. 137 (from cyclohexane/ethyl acetate).

The starting compound is produced as in Example 1 (b).

(b) Analogously to Example 1(a), the 2,3-dihydro-6- methylbenzofuran-Z-carboxylic acid is acylated with octanoyl chloride in nitrobenzene in the presence of aluminum chloride to the 2,3-dihydro-5-octanoyl-6- methyl-benzofuran-Z-carboxylic acid, M.P. 136 (from benzene).

EXAMPLE 13 (a) Analogously to Example 1(a), the 2,3-dihydro-6- ethylbenzofuran-2-carboxylic acid is acylated with butyryl chloride in nitrobenzene in the presence of aluminum chloride to the 2,3-dihydro-S-butyryI-G-ethyl-benzofuran-Z-carboxylic acid, M.P. 88 (from carbontetrachloride).

The starting compound, 2,3-dihydro-6-ethyl-benzofuran-2-carboxylic acid, is produced as follows:

(b) 50.0 g. of m-ethylphenol, 55.0 g. of malic acid and ml. of concentrated sulfuric acid are slowly heated to While stirring and stirring is continued at this temperature for 20 minutes. The reaction mixture is then poured onto 2 kg. of ice and extracted twice with 500 ml. of ether each time. The combined ether extracts are washed with 200 ml. of water and 200 ml. of concentrated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated. The residue, crude 7-ethyl coumarin, is used as crude product.

(c) 30.4 g. of 7-ethyl coumarin are dissolved in 40 ml. of chloroform and 29.0 g. of bromine in 20 ml. of chloroform are added dropwise while stirring. The temperature of the reaction mixture is kept between 20 and 25 by occasional cooling in an ice bath. The reaction mixture is then stirred for another 20 minutes at room temperature and concentrated at 50 under reduced pressure. The residue is added in portions to a solution of 80.0 g. of potassium hydroxide in ml. of ethanol, which solution has been heated to 30 and the reaction temperature is kept at 3040 by cooling. The reaction mixture is then stirred for 30 minutes at room temperature and for 30 minutes at 80, after which it is poured into 1 litre of ice water. The aqueous alkaline solution is washed twice with 300 ml. of ether each time, acidified with concentrated hydrochloric acid to pH 2-3 and the precipitated crude product is filtered off under suction. The crude product is recrystallised from ethanol and dried in vacuo at 80 whereupon the 6-ethyl-benzofuran- 2-carboXylic acid obtained melts at 152-154".

(d) Analogously to Example 1(b), 6-ethyl-benzofuran-Z-carboxylic acid is dissolved in aqueous sodium hydrogen carbonate and reduced with sodium amalgam to the 2,3-dihydro-6-ethylbenzofuran-2-carboxylic acid, M.P. 126 (from benzene).

EXAMPLE 14 (a) Analogously to Example 1(a), the 2,3-dihydro-6- fluorobenzofuran-Z-carboxylic acid is acylated with butyryl chloride in nitrobenzene in the presence of aluminum chloride to the 2,3-dihydro-5-butyryl-6-fluoro-benzo- 9 furan-Z-carboxylic acid, M.P. 144 (from cyclohexane/ ethyl acetate).

The starting compound, 2,3-dihydro-6-fluoro-benzofuran-Z-carboxylic acid, is produced as follows:

(b) 3.5 g. of p-fluoro-salicylaldehyde [cf. Hodgson, Nixon, Chem. Soc. 1635 (1929)] are refluxed with 3.5 g. of potassium carbonate in 20 ml. of methyl ethyl ketone. Then during 15 minutes, 7 g. of bromomalonic acid-diethyl ester are added dropwise. The mixture is then refluxed for 8 hours and then left standing overnight. The methyl ethyl ketone is then evaporated; the residue is treated with 30 ml. of ethanol, 3.2 ml. of water and 4 g. of potassium hydroxide and then refluxed for another 8 hours. The solution is concentrated to one third of its volume and diluted with water until a clear solution is obtained. This solution is washed with ether and then rendered acid to Congo paper with diluted sulfuric acid. The 6-fluoro-benzofuran-Z-carboxylic acid which precipitates is separated by filtration, dried and recrystallized in benzene, M.P. 263".

(c) Analogously to Example 1(b), the 6-fluoro-benzofurane-2-carboxylic acid is dissolved in aqueous sodium hydrogen carbonate and reduced with sodium amalgam to the 2,3-dihydro-G-fluoro-benzofuran-2-carboxylic acid, M.P. 142 (from benzene).

EXAMPLE 15 (a) Analogously to Example 1(a), the 2,3-dihydro-6- chloro-7-methyl-benzofuran-Z-carboxylic acid is acylated with butyryl chloride in nitrobenzene in the presence of aluminum chloride to the 2,3-dihydro-5-butyryl-6-chloro- 7-methyl-benzofuran-2-carboxylic acid, M.P. 151 (purifled by column chromatography over silica gel and with a mixture of benzene/ ethyl acetate/ acetic acid in the following proportions: 90:5 :5, and then finally recrystallized in cyclohexane).

The starting compound, 2,3-dihydro-6-chloro-7-methylbenzofurane-Z-carboxylic acid is produced as follows:

(b) 30 g. of 2-hydroxy-6-chloro-toluene [cf. Ullmann, Panchaud, A. 350, 112], 28.6 g. of malic acid and 57 ml. of concentrated sulfuric acid are heated with stirring to 90 to 100 or until no more gas generation can be detected. The mixture is then poured onto ice and extracted with ether. The ethereal solution is concentrated and the residue is recrystallized in ethanol. Greasy crystals of 7-chloro-S-methyl-coumarin are then obtained.

(c) 17.2 g. of 7-chloro-8-methyl-coumarin are suspended in 35 ml. of chloroform and at 25 4.7 ml. of bromine in 10 ml. of chloroform are added dropwise during minutes. Stirring is continued for half an hour and then the mixture is concentrated in vacuo. The residual oil is added dropwise with stirring to a solution of 39.5 g. of potassium hydroxide in 120 ml. of ethanol, taking care that the temperature does not exceed 40. Stirring is continued for 30 minutes at and then for minutes at 80. The slurry is poured onto ice. The solution obtained is adjusted to pH 7 with 4 N sulfuric acid, washed with ether, then rendered acid to Congo paper and extracted with ether. The ethereal solution is concentrated and the 6-chloro-7-methyl-benzofuran-2- carboxylic acid is recrystallised from cyclohexane/ethyl acetate, M.P. 225.

(d) Analogously to Example 1(b), the 6-chloro-7- methylbenzofuran-Z-carboxylic acid is reduced in aqueous sodium hydrogen carbonate with sodium amalgam to the 2,3-dihydro-6-chloro 7 methylbenzofuran-Z-carboxylic acid, M.P. 133 (from cyclohexane/ethyl acerate).

EXAMPLE 16 (a) Analogously to Example 1(a), the 2,3-dihydro-6- methylbenzo[b]thiophene-Z-carboxylic acid is acylated with butyryl chloride in nitrobenzene in the presence of aluminum chloride to the 2,3-dihydro-5-butyryl-6-methylbenzo[b]thiophene-2-carboxylic acid, M.P. 122 (from carbon tetrachloride).

The starting compound 2,3-dihydro-6-methyl-benzo[b] thiophene-Z-carboxylic acid is produced as follows:

(b) Analogously to Example 1(b), the fi-methyl-benzo [b]thiophene-2-carboxylic acid is reduced in aqueous sodium hydrogen carbonate with sodium amalgam to the 2,3-dihydro'6-methyl-benzo[b]thiophene 2 carboxylic acid, M.P. 158 (from cyclohexane).

EXAMPLE 17 (a) Analogously to Example 1(a), 2,3-dihydro-6- chlorobenzob1thiophene-2-carboxylic acid is acylated with butyryl chloride in nitrobenzene in the presence of aluminum chloride to the 2,3-dihydro-5-butyryl-6-chlorobenzo [b] thiophene-Z-carboxylic acid.

The starting acid is produced as follows:

(b) A mixture of 96 g. of rhodanine, 169 g. of anhydrous sodium acetate and 450 ml. of glacial acetic acid are heated to To the solution formed, 126 g. of 2,4- dichlorobenzaldehyde, dissolved in 225 ml. of glacial acetic acid, are added dropwise. A slurry is formed which is then refluxed for 30 minutes. The hot mixture is then poured into 5 litres of ice water. The 2-thioxo-5-(2,4-dichlorobenzylidene) 4 thiazolidinone-[5-(2,4dichlorobenzylidene)-rhodanine] which precipitates is suction filtered and rinsed with Water.

(c) This crude substance is dissolved by heating in 2 litres of 5% aqueous sodium hydroxide, then cooled again, whereby traces of 2,4-dichlorobenzaldehyde precipitate which are separated by filtration. Concentrated hydrochloric acid is quickly added in excess to the solution, which is cooled again and the 2,4-dichloro-ot-mercapto-cinnamic acid which precipitates is separated by filtration. This acid is taken up in ether, then this solution is dried with sodium sulfate and concentrated.

(d) The residue is heated with 1350 ml. of diethylene glycol and 117 g. of sodium methylate to ISO- (inner temperature) and stirred for one hour at this temperature, whereby methanol distills 0E. The mixture is then poured onto 5 litres of ice and rendered acid to Congo paper with hydrochloric acid. 6-chloro-benzo[b]thiophene-Z-carboxylic acid precipitates which is separated by filtration and recrystallised in dioxane/ethyl acetate, M.P. 283.

The 6 chloro-benzo[b]thiophene-2-carboxylic acid is reduced analogously to Example 1(b) to 2,3-dihydro-6- chloro benzo[b]thiophene 2 carboxylic acid, M.P. 1968.

EXAMPLE 18 (a) Analogously to Example 1(a), the 2,3-dihydro-4- chlorobenzo [b]thiophene-2-carboxylic acid is acylated with butyryl chloride to the 2,3-dihydro-4-chloro-5-bu tyryl-benzo [b]thiophene-2-carboxylic acid, M.P. 178 (from methanol).

The starting compound is produced as follows:

(b) Analogously to Example 17(b), 2-thioxo-5-(2,6- dich'lorobenzylidene)-(4)-thiazolidinone is produced from 2,6-dichlorobenzaldehyde and rhodanine in the presence of sodium acetate and glacial acetic acid.

(c) This thiazolidinone is then treated analogously to Example 17(c), whereby, however, by refluxing for 10 hours, 4-chloro-benzo[b]thiophene 2 carboxylic acid, M.P. 2579 (from ethanol), is obtained in one step. This acid is reduced analogously to Example 16 to the 2,3-dihydro-4-chloro-benzo[b]thiophene 2 carboxylic acid, M.P. l58160 (from benzene).

EXAMPLE 19 (a) Analogously to Example 1(a), the 2,3-dihydro-6 ethoxybenzo[b]thiophene-Z-carboxylic acid is acylated with butyryl chloride to the 2,3 dihydro-5-butyryl-6- ethoxy-benzo[b]thiophene-2-carboxylic acid, M.P. 144 (from benzene).

The starting compound is produced as follows:

(b) 389 g. of 6-ethoxy-benzo[blthiophene-3(2H)-one are suspended in 1750 ml. of isopropanol and heated to 35. Then 76 g. of sodium borohydride are added and the mixture is left to stand about 15 hours. After dilution with 1500 ml. of water, the solution is extracted with ether. Concentration of the ether leaves 400 g. of violet crystals which are triturated for one hour with 700 g. of polyphosphoric acid. After the addition of excess ice, 6- ethoxy-benzo[b]thiophene is extracted with ether and then distilled, B.P. 120/0.1 torr.

(c) Under nitrogen, 320 g. of 20% butyl lithium in hexane are diluted with 1000 ml. of ether and cooled to -15 to 20. Then 108 g. of 6-ethoxy-benzo[b]thiophene, dissolved in 800 ml. of ether, are added dropwise with stirring during one hour. The resulting mixture is poured onto 4000 g. of Dry Ice which has been slurried in 2000 m1. of ether. After slowly warming to room temperature, it is rendered acid to Congo paper with hydrochloric acid, extracted with ether and then concentrated, whereby 6 ethoxy-benzo[b]thiophene-Z-carboxylic acid, M.P. 208-211 (from ethanol), remains.

(d) The 6-ethoxy-benzo[b]thiophene-Z-carboxylic acid is reduced analogously to Example 1(b) to the 2,3-dihydro-G-ethoxy-benzo[b]thiophene-2-carboxylic acid, M.P. 118-419".

EXAMPLE 20 12.6 g. of the 2,3-dihydro-6-methylbenzofuran-Z-carboxylic acid are dissolved in 70 ml. nitrobenzene and during 30 minutes with stirring and cooling are added 35 g. aluminium chloride in portions. The temperature must be maintained under 10. At the same tempertaure, 16 g. butyryl bromide are dropped in during 30 minutes.

The reaction mixture is then further stirred for hours in an ice bath, allowed to stand for 16 hours at room temperature, heated for a further hour to 40 and then poured on to 500 g. of ice. To the obtained suspension are added 50 ml. of concentrated hydrochloric acid. After the aluminium chloride complex has thus been decomposed the reaction mixture is extracted three times with, each time, 150 ml. of ether. The ether extract is dried over sodium sulphate and concentrated by evaporation. The residue is slurried in hexane, shaken up, again separated from the hexane and recrystallised from benzene. The obtained 2, 3 dihydro-S-butyryl-methylbenzofuran-Z-carboxylic acid melts at 140141.

EXAMPLE 21 12.6 g. of 2,3-dihydro-6-methylbenzofuran-Z-carboxylic acid are dissolved in 70 ml. nitro benzene and 35 g. aluminium chloride are added in portions during 30 minutes with stirring and cooling. The temperature must be maintained at below At the same temperature, 16.5 g. butyric acid anhydride is dropped in during 30 minutes.

The reaction mixture is then further stirred for 5 hours in an ice bath, allowed to stand for 16 hours at room temperature, heated for a further hour to 40 and then poured onto 500 g. of ice. To the obtained suspension are added 50 ml. of concentrated hydrochloric acid. After the aluminium chloride complex has thus been decomposed the reaction mixture is extracted three times with, each time, 150 ml. of ether. The ether extract is dried over so dium sulphate and concentrated by evaporation. The residue is slurried in hexane, shaken up, again separated from the hexane and recrystallised from benzene. The obtained 2,3-dihyd-ro-S-butyryl-6-methylbenzofuran 2 carboxylic acid melts at 140-141 EXAMPLE 22 Analogously to Example 1(a), the 2,3-dihydro-2,3 dimethyl benzofuran-Z-carboxylic acid (cp. Russell Gaertner J. Am. Chem. Soc. 74, 5319 (1952)) are acylated with butyric acid chloride in nitro benzene in the presence of aluminium chloride to the 2,3-dihydro-2,3-dimethyl-5- butyryl-benzofuran-2-carboxylic acid, M.P. 110-113".

EXAMPLE 23 1000 g. of 2,3-dihydro-5-butyryl-6-methyl-benzofuran- 2-carboxylic acid are mixed with 550 g. of lactose and 292 g. of potato starch. The mixture is moistened with an aqueous soltuion of 8 g. of gelatine and granulated through a sieve. After drying, 60 g. of potato starch, 60 g. of talcum, 10 g. of magnesium stearate and 20 g. of colloidal silicon dioxide are mixed in.

The mixture is pressed into 10,000 tablets each Weighing 200 mg. and each containing mg. of active substance. Optionally, the tablets can be provided with grooves for a more accurate adjustment of the dosage amount. As active substance the same amount of S-butyryl 2,3 dihydro-6,7-dimethyl-benzofuran-Z-carboxylic acid can also be used.

EXAMPLE 24 A granulate is produced from 1000 g. of 2,3-dihydro- 5-butyry1-6-methylbenzofuran-2-carboxylic acid, 379 g. of lactose and the aqueous solution of 6 g. of gelatine. After drying, the granulate is mixed with 10 g. of colloidal silicon dioxide, 40 g. of talcum, 60 g. of potato starch and 5 g. of magnesium stearate and the mixture pressed into 10,000 drage cores. These are subsequently coated with a concentrated syrup made from 533.5 g. of crystallised saccharose, 20 g. of shellac, 75 g. of gum arabic, 250 g. of talcum, 20 g. of colloidal silicon dioxide and 1.5 g. of dyestutf, and dried. The obtained drages each weigh 240 mg. and each contain 100 mg. of active substance.

EXAMPLE 25 100 g. of 2,3-dihydro-5-butyryl-6-methylbenzofuran-2- carboxylic acid are mixed with 9.5 g. of talcum and 0.5 g. of magnesium stearate and the mixture is put through a sieve (e.g. Sieve IV, Ph, Helv. V). Capsules of size 0 are then filled from the mixture. In this way 1000 capsules each containing mg. of active substance are produced. As active substance can also be used the same amount of 5-butryl-2,3-dihydro-6,7-dimethyl-benzofuran 2 carboxylic acid.

EXAMPLE 26 1.5 litres of glycerin, 42 g. of p-hydroxy-benzoic acid methyl ester, 18 g. of p-hydroxybenzoic acid propyl ester and, while heating slightly, 50 g. of 2,3-dihydro-5-butyry1- '6-methylbenzofuran-2-carboxylic acid are dissolved in 3 litres of distilled water. To this are added 4 litres of 70% sorbitol solution, 1000 g. of crystallised saccharose, 350 g. of glucose and an aromatic, e.g. 250 g. of Orange Peel Soluble Fluid of Eli Lilly and Co., Indianapolis, or 5 g. of natural lemon aroma and 5 g. of Halb und Halb essence, both from the firm Haarmann und Reimer, Holzminden, Germany. The obtained solution is filtered and the filtrate made up to 10 litres with distilled water, so as to produce a cough syrup having a content of active substance of 0.5%.

EXAMPLE 27 To prepare cough drops having an active substance content of 2.5%, 250 g. of 2,3-dihydro-5-butyryl-6-methylbenzofuran-Z-carboxylic acid and 30 g. of sodium cyclamate are dissolved in a mixture of 4 litres of ethanol (96%) and 1 litre of propylene glycol. At the same time, 3.5 litres of 70% sorbitol solution are mixed with 1 litre of water and the mixture is added to the above active substance solution. An aromatic is then added, e.g. 5 g. of cough-drop aroma or 30 g. of Grapefruit Essence, both from the firm Haarmann und Reimer, Holzmindcn, Germany. The whole is well mixed, filtered and made up to 10 litres with distilled Water.

EXAMPLE 28 A suppository mixture is prepared from 2.5 g. of 2,3- dihydro 5-butyryl-G-methylbenzofuran-Z-carboxylic acid and 167.5 g. of adeps solidus. From the mixture are poured 100 suppositories each containing 25 mg. of active substance.

13 EXAMPLE 29 wherein R is alkyl having from 2 to 7 carbon atoms, Y is hydrogen, methyl or methoxy, Y is hydrogen or methyl and Z and Z independently, are hydrogen, chloro, fluoro, bromo, methyl, ethyl, methoxy or ethoxy and pharmaceutically acceptable salts thereof with bases.

2. A compound according to claim 1 which is 2,3-dihydro-5-bntyry1-6-methy1-benzo[blthiophene-Z-carboxylic acid.

3. A compound according to claim 1 which is 2,3-dihydro -5-butyryl-6-chloro-benzo [b] thiophene-Z-carbonylic acid.

4. A compound according to claim 1 which is 2,3-dihydro-4-chloro-S-butyryl-benzo[bjlthibphene-Z-carboxylic acid.

5. A compound according to claim 1 which is 2,3-dihydro-S-butyryl- 6-ethoxy-benzo [b] thiophene-Z-carboxylic acid.

References Cited HENRY R. JILES, Primary Examiner C. M. S. JAISLE, Assistant Examiner US. Cl. X.R. 

